The Mode of Action and Clinical Outcomes of Sacituzumab Govitecan in Solid Tumors

Abstract

Sacituzumab govitecan (SG), a trophoblast cell-surface antigen-2 (Trop-2)–directed antibody–drug conjugate, is currently approved to treat metastatic triple-negative breast cancer and HR⁺/HER2⁻ breast cancer and is under clinical investigation for a range of other tumor types. This review describes its mode of action, development, and clinical outcomes. SG is composed of SN-38 (a topoisomerase I inhibitor derived from irinotecan) covalently linked to an anti–Trop-2 mAb (sacituzumab; hRS7) via a hydrolyzable CL2A linker. SN-38 was chosen due to its potent antitumor activity; CL2A occupies the most effective position on SN-38 for maintaining stability during transport, with pH-sensitive payload release in the tumor, and the antigen target (Trop-2) is highly expressed on many solid tumors. SG has an ∼8:1 drug-to-antibody ratio and delivers therapeutic SN-38 concentration to Trop-2⁺–expressing tumor cells via rapid internalization and efficient payload release. Free SN-38 can subsequently enter the tumor microenvironment and kill adjacent tumor cells with or without Trop-2 expression (bystander effect). SN-38 induces DNA breakage and inhibits nucleic acid synthesis via a drug-induced topoisomerase 1:DNA complex that interferes with cell proliferation, causing apoptosis. Dose-finding studies support SG 10 mg/kg on days 1 and 8 of a 21-day cycle as the monotherapy dose for clinical use; this was determined by therapeutic index improvement based on efficacy and safety. Payload–linker dynamics and SG potency ensure continued tissue penetration. Neutropenia and diarrhea are the most common grade ≥3 treatment-emergent adverse events with SG, but they are manageable. The efficacy of SG has been demonstrated across a broad spectrum of solid tumors.

Introduction

Antibody–drug conjugates (ADC) are innovative cancer treatments composed of a tumor-targeting humanized mAb attached to a small-molecule cytotoxic drug (payload) via a chemical linker. These components are designed to work synergistically; the mAb is directed to an antigen that is highly expressed on tumor cells, the linker should be stable enough to ensure that sufficient payload is transported to the tumor site, and the payload itself is cytotoxic (1).

Several ADCs have been approved by the U.S. FDA as cancer therapies. These ADCs (summarized in Supplementary Table S1) can be categorized based on the primary action of their payload (2). However, their development has been challenging. Some earlier ADCs exhibited issues related to noncleavable linkers that lacked cell permeability or unstable, cleavable linkers that released payloads into the nontumorous environment, resulting in off-tumor toxicity (3). Rapid linker degradation can also result in a poor drug-to-antibody ratio (DAR) in the tumor, limiting ADC effectiveness (3).

Sacituzumab govitecan (SG; hRS7-CL2A-SN-38; Trodelvy) is a next-generation ADC designed to improve payload delivery to the tumor. It is approved in patients with unresectable, locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease, and for patients with unresectable, locally advanced or metastatic hormone receptor–positive (HR⁺), HER2-negative (HER2⁻; IHC 0, 1+ or 2+/in situ hybridization–negative) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting (4). This review will provide an overview of SG in solid tumors, focusing on its mode of action.

SG

SG emerged as an effective trophoblast cell-surface antigen-2 (Trop-2) tumor-directed ADC with high specificity for solid tumors during a development process described herein. SG is composed of SN-38 (govitecan) covalently linked to an anti–Trop-2 IgG1-k mAb (sacituzumab; hRS7) via a proprietary, hydrolyzable CL2A linker (4).

Properties of SN-38

Irinotecan is a prodrug that is hepatically converted to SN-38, which is 100- to 1,000-fold more biologically active than its parent molecule (5, 6). SN-38 inhibits topoisomerase I, a key enzyme complex involved in DNA transcription and replication (7). This causes irreversible double-strand DNA breakage, resulting in tumor cell death. SN-38 is ultimately converted to its inactive form (SN-38 glucuronide) primarily by UGT1A1-mediated glucuronidation in the liver prior to excretion in bile (7, 8).

The efficacy of SN-38 is dependent on an intact cytotoxic lactone ring, which is stable at pH ≤ 4.5 (9). The much less pharmacologically active carboxylate form (which has an open lactone ring) becomes dominant at normal physiologic pH 7.4 as it forms a stable complex with serum albumin (9–11). This pH-dependent hydrolysis of SN-38 and its poor solubility made it historically unsuitable for systemic administration, and approaches to improve its solubility have met with mixed success (9).

SG was the first ADC to harness the potency of SN-38 for systemic administration, overcoming the challenges faced by earlier drug development (12–15). Exposure (AUC) over a 3-week cycle is more than 15-fold higher with SG 10 mg/kg than irinotecan 340 mg/m² (20 vs. 1.2 μmol/L × hours), and because of this increased AUC, SG can deliver 20- to 136-fold more SN-38 to tumors than irinotecan (16, 17). Furthermore, time spent over the target concentration of SN-38 needed to inhibit topoisomerase I (∼10 nmol/L) is longer with SG than irinotecan [7.5 vs. 4.4 days (over a 3-week period); ref. 17].

Linker development

Early SN-38 ADCs targeted carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) rather than Trop-2. This glycosylphosphatidylinositol-anchored glycoprotein is highly expressed in colorectal cancer, making it an ideal target given the proven efficacy of irinotecan in colorectal cancer (8, 18, 19). These early ADCs were composed of the anti-CEACAM5 antibody labetuzumab (hMN-14) as the delivery system for SN-38 using cleavable linkers (8, 20).

Initially, three cleavable linkers (CL1, CL2, and CL3) that varied in their attachment to SN-38’s 20-hydroxyl group were further investigated in these early SN-38 ADCs. The 20-hydroxyl group plays an important role in the biological activity of SN-38 as it is attached to the active cytotoxic lactone ring. Attachment of linkers to this area maintains SN-38 in its active lactone form, regardless of pH conditions, and SN-38 remains protected from inactivation via glucuronidation while it is conjugated to the antibody via the linker. This improves its stability and potency by enabling SN-38 to remain in situ during systemic transport with maximal payload release in the acidic tumor lysosome (14, 20, 21).

Of these early ADCs, labetuzumab-CL2-SN-38 was associated with greater tumor growth suppression and increased survival in xenograft models at nontoxic doses (20). Thus, the CL2 linker was further studied along with a modified version, known as CL2A. Both linkers were designed to have a short, noncleavable polyethylene glycol moiety that confers aqueous solubility, and nonspecific ADC uptake and off-target toxicity may be reduced via this hydrophilicity (12, 14, 22). These linkers were also designed to allow targeted and rapid release of SN-38 via cleavage of a low pH-sensitive benzyl carbonate bonded to SN-38’s intact lactone ring (12, 23, 24). Ultimately, the CL2A linker was chosen for SG as it does not contain a phenylalanine moiety, which improved conjugate quality and simplified large-scale synthesis (12).

Trop-2

In parallel to the work with CEACAM5, interest in a broad-spectrum tumor-associated antigen, Trop-2 [coded by the tumor-associated calcium signal transducer 2 (TACSTD2) gene], was growing (12, 14, 25). Trop-2 is a 36-kDa transmembrane glycoprotein anchored to the cell surface via a unidirectional transmembrane helix (25, 26); it is involved in regulating cell signaling pathways, including cyclin D1, NF-kB, and extracellular regulated protein kinases (ERK)/mitogen-activated protein kinase (MAPK). It is via these pathways that the TACSTD2 gene regulates cancer growth and invasion, and Trop-2 is highly expressed on a variety of solid tumor types (27). Although Trop-2 is not highly expressed in normal tissues, it is still involved in essential cell processes, including maintenance of tight junction integrity, and loss of Trop-2 can affect the performance of epithelial barriers (27).

A mouse-derived mAb (RS7) that binds human Trop-2 protein across a range of cancer types was identified (28). RS7 was then successfully humanized (hRS7) and tested in human xenograft studies as radioimmunotherapy (RAIT; ref. 29). Radioactive labeled hRS7 (¹³¹I-IMP-R4-hRS7) was specific for tumors, and an effective dose could be delivered to the tumor to enable significant regression of a breast tumor xenograft in mice (29). Although RAIT had demonstrated efficacy in preclinical models, this did not translate into clinical efficacy until much later. The failure of RAIT as a therapeutic approach at the time was attributable to the inherent resistance of bulky, solid tumors to irradiation (30). As a result, investigational focus shifted to ADCs as the payload modality.

hRS7 was then conjugated to CL2-SN-38, and this was tested in five solid tumor xenograft models with Trop-2 expression that was comparable with human tumor cells. These two derivatives were equivalent in drug substitution, cell binding, cytotoxicity, and serum stability in vitro, and they exhibited antitumor effects in solid tumors at nontoxic doses (12). When placed in serum at 37°C, SN-38 was released from the hRS7-CL2A linker with a half-life of ∼24 hours (12, 13). SN-38 is a potent topoisomerase I inhibitor and can tolerate a drug-linker with a shorter half-life to enable this optimal therapeutic window, i.e., tissue penetration can be maintained with lower toxic accumulation than other ADCs.

Delivery of SN-38 via SG to Trop-2-expressing tumor xenografts achieved a 20- to 136-fold higher concentration of SN-38 at the tumor compared with systemic administration of irinotecan, with tumor:blood ratios favoring SG by 20- to 40-fold (16). SG has a consistent DAR of ∼8:1 (i.e., SN-38 conjugation occurs at eight regions on the antibody), demonstrating that the conjugation of SN-38 to hRS7-CL2A did not adversely affect the delivery of high payload concentrations, and this high DAR delivers potent antitumor activity (12, 13).

Trop-2 Binding

hRS7 can recognize and bind to Trop-2, a target that is highly expressed on many solid tumor types. Postinjection, the amount of naked hRS7 antibody will increase relative to intact SN-38–conjugated SG; however, the hydrophobic nature of SN-38 may help to displace water molecules from around the binding epitope, enabling a binding advantage of SN-38–conjugated hRS7 over naked hRS7 (13).

The relationship between SG efficacy and Trop-2 expression is complex. Trop-2 overexpression is thought to protect cancer cells from apoptosis as it can modulate cell adhesion via 3-MAPK/ERK1 pathways (31). Increasing Trop-2 expression is also correlated with poor survival in patients with solid tumors (32). SG is effective in tumors with high Trop-2 as more binding sites enable a higher concentration of SN-38 to access the tumor. Although most cancer types have overexpression of Trop-2, SG also exhibits clinical benefit in tumors with very low Trop-2. In the ASCENT study of patients with previously treated mTNBC, SG was associated with greater survival benefits versus single-agent chemotherapy treatment of physician’s choice (TPC) across all levels of Trop-2 expression (low, n = 59; medium, n = 74; and high, n = 157; ref. 33). The median overall survival was 14.2, 14.9, and 9.3 months with SG versus 6.9, 6.9, and 7.6 months with TPC in patients with high, medium, and low Trop-2 scores (defined by IHC H-score ranges), respectively. Similar findings were observed in the TROPiCS-02 study, in which patients with HR⁺/HER2⁻ metastatic breast cancer (mBC) received SG or TPC (34). These findings support that Trop-2 testing is not needed to determine patient eligibility for SG, as there is a treatment benefit regardless of Trop-2 expression. The effect of SG in tumors with low Trop-2 may be explained by its high DAR, low nanomolar Trop-2 binding affinity, sensitivity of cancer cells to SN-38, and the bystander effect (described later).

Pharmacodynamic Mode of Action

Internalization and DNA damage

The pH-dependent properties of the CL2A linker are conducive to antibody-induced, receptor-mediated SG internalization to lysosomes. Rapid and efficient release of SN-38 via linker hydrolysis predominantly occurs in the acidic lysosome when the drug is no longer conjugated to humanized mAbs (Fig. 1; refs. 4, 12–15, 23). Although most SN-38 is distributed as IgG-bound SN-38, approximately 2.5% of the total payload is released as free (systemic) SN-38, which can be quickly converted to SN-38G via UGT1A1 glucuronidation (16, 35). IgG-bound SN-38 is protected from prompt clearance via UGT1A1-mediated conversion. Thus, SG may reduce the potential for off-target side-effects in addition to increased efficacy versus irinotecan (16, 35).

Figure 1.

Mode of action of SG (4, 12–15, 23). TOP I, topoisomerase I.

Once internalized, SN-38 induces DNA breakage and inhibits nucleic acid synthesis via a drug-induced topoisomerase 1:DNA complex that destroys proliferating cells (15, 36, 37). Significant antitumor effect has been consistently demonstrated through in-vivo studies utilizing solid tumor xenografts (23, 38–40). Tumor cells will try to minimize this DNA damage by excising the topoisomerase 1:DNA complex, leading to single-strand DNA breakage and repair by PARP (15, 41). Any remaining double-stranded DNA breaks will be repaired by homologous recombination repair (HRR) or by nonhomologous end-joining.

SG produced significant tumor regression in mice bearing irinotecan-resistant TNBC tumors that expressed high Trop-2 with proficient HRR DNA repair (15). Thus, HRR may have prognostic value for treatment response in addition to other predictors, such as Schlafen 11, which is linked with increased sensitivity to any cancer treatments that target DNA (15, 42).

Because topoisomerase I catalytic activity and cell proliferation are slower in normal tissues, the risk of toxicity on healthy tissue expressing Trop-2 is lower than cancerous cells (43). Also, normal tissues predominantly have a pH > 7.0 compared with the more acidic tumor microenvironment. This would impact SG as follows: (i) SN-38 released in the tumor will favor the more active lactone form, and (ii) released SN-38 will be taken up by tumor cells at significantly greater efficiency compared with normal cells in the higher pH microenvironment (44, 45). In addition, the luminal edge of ducts and glands expressing Trop-2 are likely to be poorly accessible to large molecules such as antibodies or ADCs (14), and free SN-38 may have less impact on these normal tissues than on dividing tumor cells (46).

Bystander Effect

Once internalized, the CLA2 linker allows release of SN-38 directly into the Trop-2–expressing tumor cell and subsequently into the tumor microenvironment and neighboring tumor cells, which is known as the bystander effect. This was demonstrated using in vitro studies of admixed cells with high or low/negligible Trop-2 expression. When these cells were administered SG, both cell types were killed (38–40, 47). The hydrolyzable CL2A linker is thought to enable the bystander effect in SG as it was not observed with a control hRS7-ADC using a stable cathepsin B linker (hRS7-CL2E-SN-38; refs. 23, 24).

Dosing Schedule

In the IMMU-132-01 study of patients with diverse cancers, dose escalation was based on planned initial SG doses of 8, 12, and 18 mg/kg. SG 12 mg/kg was formally identified as the maximum tolerated dose but was associated with dose delays and reductions in several patients (48). There were no major differences in safety [worsening of adverse event (AE) incidence or severity] between the 8 and 10 mg/kg doses for all tumors studied, but there was a trend for better efficacy in patients with mTNBC with SG 10 mg/kg (35). Based on these results, as well as schedules explored in the labetuzumab–CL2A–SN-38 phase II studies, and to ensure treatment was timed for the S-phase of the cell cycle (when SN-38 is most active; ref. 49), SG 10 mg/kg on days 1 and 8 of a continuous 21-day cycle was selected as the optimal schedule to maintain tissue penetration.

Clinical Experience

Efficacy outcomes for the pivotal clinical studies (ASCENT and TROPiCS-02) that supported the approval of SG in mTNBC and HR⁺/HER2⁻ mBC are summarized in Table 1 (48, 50–60) and Fig. 2 (50–55, 61, 62). Also shown are the survival outcomes with SG in the second-line or later setting in other solid tumors, including non–small cell lung cancer and urothelial cancer (Supplementary Table S2).

Table 1.

Overview of sponsor-initiated SG studies.

Study	Design	Patients receiving SG (n)	Tumor type	Median age, years	Female, %	Treatment/prior LOT	Primary outcome(s)
TNBC
IMMU-132-01 [Bardia and colleagues (50)]	Single-arm, open-label, phase I/II basket study	108	Refractory mTNBC	55	99	SG/≥2	ORR; TEAEs; and discontinuation due to AEs
ASCENT [Bardia and colleagues (51)]	Randomized, open-label, phase III study	235	Relapsed/refractory mTNBC	54	99	SG vs. single-agent CT/≥2	PFS by BICR among patients without brain metastases (n = 468)
EVER-132-001 [Xu and colleagues (52)]	Single-arm, open-label, phase IIb study in Chinese patients	80	mTNBC	48	100	SG/≥2	ORR; TEAEs; and discontinuation due to AEs
HR + /HER2 − breast cancer
IMMU-132-01 [Kalinsky and colleagues (53)]	Single-arm, open-label, phase I/II basket study	54	Previously treated HR+/HER2− mBC	54	100	SG/≥2	ORR; TEAEs; and discontinuation due to AEs
TROPiCS-02 [Rugo and colleagues (54)]	Randomized, open-label, phase III study	272	Inoperable, locally advanced, or metastatic HR+/HER2− breast cancer	57	99	SG vs. physician’s choice CT/2-4	PFS by BICR
EVER-132-002 [Xu and colleagues (55)]	Randomized, open-label, phase III study in Asian patients (China, Korea, Taiwan)	166	Endocrine-resistant HR+/HER2− mBC	53	100	SG vs. physician’s choice CT/2-4	PFS by BICR
UC
IMMU-132-01 [Tagawa and colleagues (48); Bardia and colleagues (56)]	Single-arm, open-label, phase I/II basket study	45	Previously treated metastatic UC	67	9	SG/≥2	ORR; TEAEs; and discontinuation due to AEs
TROPHY-U-01 C1 [Loriot and colleagues (57)]	Open-label, phase II study	113	Locally advanced, unresectable, or metastatic UC	66	22	SG/≥1a	ORR by BICR
TROPHY-U-01 C2 [Petrylak and colleagues (58)]	Open-label, phase II study	38	Locally advanced, unresectable, or metastatic UC	73	39	SG/≥1a	ORR by BICR
TROPHY-U-01 C3 [Grivas and colleagues (59)]	Open-label, phase II study	41	Locally advanced, unresectable, or metastatic UC	67	17	SG + pembrolizumab/≥1a	ORR by BICR
NSCLC
EVOKE-01 [Paz-Ares and colleagues (60)]	Randomized, open-label, phase III study	299	Advanced or metastatic NSCLC	66	35	SG vs. docetaxel after progression on platinum-based CT and CPI given as combination or sequential therapy	OS

In all studies, SG was administered as an i.v. infusion of 10 mg/kg on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity except in IMMU-132-01, in which the overall population received SG 8, 10, 12, or 18 mg/kg.

Abbreviations: BICR, blinded independent central review; CT, chemotherapy; LOT, line of therapy; NSCLC, non–small cell lung cancer; OS, overall survival; UC, urothelial carcinoma.

^aIn the metastatic setting.

Figure 2.

Survival outcomes in SG studies in approved indications (50–55, 61, 62). CI, confidence interval; LOT, line of therapy; NA, not assessable; NE, not estimable; NR, not reached; OS, overall survival.

Safety Considerations

The most common treatment-related AEs (TRAE) observed in clinical studies of SG were neutropenia, diarrhea, nausea, and fatigue (Fig. 3; refs. 48, 50–55, 57–60). In a pooled safety analysis of 1,063 patients treated with SG (10 mg/kg, days 1 and 8 every 21 days) enrolled in four clinical studies (ASCENT, TROPiCS-02, TROPHY-U-01, and IMMU-132-01), the most common grade ≥3 TRAEs were neutropenia (46%), anemia (12%), leukopenia (11%), and diarrhea (11%), with dose reductions due to AEs in 31% and SG discontinuations in 7% of patients (63). These events are similar to those of the payload backbone, although their severity is expected to be lower (22).

Figure 3.

Most common grade ≥3 TRAEs in key SG studies (48, 50–55, 57–60). LA/mUC, locally advanced, unresectable, or metastatic urothelial cancer; WBC, white blood cells. TRAEs include SG-related TRAEs. Patients received SG plus pembrolizumab in TROPHY-U-01 C3.

The most common AEs associated with SG are manageable using well-established guidance, including for those patients with UGT1A1 deficiencies. Of note, the open-label PRIMED study showed that primary prophylactic administration of granulocyte colony-stimulating factor and loperamide in 50 patients with breast cancer reduced the incidence and severity of SG-related neutropenia and diarrhea and reduced dose reductions and discontinuations (64).

Resistance

Although an in-depth discussion of resistance is outside the scope of this article, it is important to note that cancer drug resistance is often multifactorial. ADC resistance is not currently well understood. Resistance mechanisms have been postulated to be either de novo or acquired and could be driven by antibody or payload-mediated resistance, impaired internalization attributed to compromised endocytosis, or disrupted lysosome function (65). Antibody-mediated resistance may involve the loss of target receptor expression for some ADCs (65). However, this would not fully explain acquired resistance in patients with mTNBC (HR⁻/HER2⁻) or HER2-low/zero tumors or the efficacy of SG in patients with low Trop-2 expression. In a report exploring SG resistance in three patients with TNBC, undetectable Trop-2 expression was associated with de novo resistance, and topoisomerase 1 or TACSTD2/Trop-2 genomic mutations were evidenced in acquired resistance (66). Acquired resistance to SG may also be associated with defective Trop-2 localization, ABCG2/BCRP drug efflux pump, or UGT1A1 mutations (67, 68).

Future Directions

SG is being further investigated in earlier lines of therapy (e.g., ASCENT-03, ASCENT-04, ASCENT-07, EVOKE-03, and VELOCITY-Lung) and in different tumor types and settings (Table 2). Many other SG studies are ongoing; these include studies in head and neck squamous cell cancer, small cell lung cancer, and endometrial cancer (TROPiCS-03; NCT03964727). SG is under investigation as monotherapy in the second-line or later setting in patients with metastatic colorectal cancer (TROPHIT1; NCT06243393), metastatic gastroesophageal adenocarcinoma (NCT06123468), metastatic cholangiocarcinoma (NCT06178588), and advanced esophageal squamous cell cancer (NCT06329869) and as combination therapy with capecitabine in advanced cancer (e.g., pancreaticobiliary cancer) after progression on first-line chemotherapy (NCT06065371). The SASCIA study (NCT04595565) is exploring the efficacy and safety of SG in patients with HER2⁻ breast cancer with residual disease after neoadjuvant chemotherapy.

Table 2.

Overview of ongoing/recruiting sponsor-initiated SG studies.

Study	Design	Tumor type	Treatment	Primary outcome(s)
TNBC
ASCENT-03 (NCT05382299)	Randomized, open-label, phase III study	Locally advanced, inoperable, or mTNBC tumors that are PD(L)-1–negative and untreated or PD(L)-1–positive and treated with CPI in the (neo)adjuvant setting	SG vs. TPC	PFS by BICR
ASCENT-04 (NCT05382286)	Randomized, open-label, phase III study	Locally advanced, inoperable, or mTNBC tumors that are PD(L)-1–positive and untreated	SG plus pembrolizumab vs. TPC plus pembrolizumab	PFS by BICR
ASCENT-05 (NCT05633654)	Randomized, open-label, phase III study	Residual invasive TNBC after surgery and neoadjuvant therapy	SG + pembrolizumab vs. TPC	Invasive disease-free survival
HR + /HER2 − breast cancer
ASCENT-07 (NCT05840211)	Randomized, open-label, phase III study	Chemotherapy-naïve, inoperable, locally advanced, or metastatic ET-resistant HR+/HER2− breast cancer	SG vs. TPC	PFS by BICR
NSCLC
EVOKE-02 (NCT05186974)	Open-label, phase II study	Untreated metastatic NSCLC	SG + pembrolizumab ± platinum agent	ORR by BICR
EVOKE-03 (NCT05609968)	Randomized, open-label, phase III study	Untreated metastatic NSCLC with PD(L)-1 tumor proportion score ≥50%	SG + pembrolizumab vs. pembrolizumab monotherapy	PFS by BICR and OS
VELOCITY-Lung (NCT05633667)	Randomized, open-label, phase III platform study	Substudy 01: Untreated metastatic NSCLC	Substudy 01: Zimberelimab + domvanalimab + SG or etrumadenant/zimberelimab + etrumadenant vs. zimberelimab + platinum-based chemotherapy	Substudies 01 and 02: ORR
		Substudy 02: Treated, progressed metastatic NSCLC	Substudy 02: SG + zimberelimab + etrumadenant vs. docetaxel or SG
Pan- tumors
ASCENT J-02 (NCT05101096)	Open-label, phase I/II, dose escalation/expansion study in Japanese patients	Phase I: Advanced solid tumors	SG monotherapy	Phase I: Safety, incidence of dose-limiting toxicities, and determination of RP2D
		Phase II: mTNBC, HR+/HER2– mBC, and metastatic urothelial carcinoma		Phase II: ORR by IRC
TROPiCS-03 (NCT03964727)	Open-label, phase II study	NSCLC, HNSCC, mSCLC, and endometrial cancer	SG monotherapy	ORR
EVER-132-003 (NCT05119907)	Open-label, phase II study	Solid tumors	SG monotherapy	ORR

In all studies, SG was administered as an i.v. infusion of 10 mg/kg on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity except in IMMU-132-01, in which the overall population received SG 8, 10, 12, or 18 mg/kg, and in ASCENT J-02, in which the phase I population received SG 6 mg/kg, escalating to 10 mg/kg.

Abbreviations: BICR, blinded independent central review; ET, endocrine therapy; HNSCC, head and neck squamous cell carcinoma; IRC, independent review committee; mSCLC, metastatic small cell lung cancer; NSCLC, non–small cell lung cancer; ORR, objective response rate; OS, overall survival; RP2D, recommended phase 2 dose.

Source: ClinicalTrial.gov (Accessed October 2024).

The combination of SG and an immune checkpoint inhibitor (CPI) is the focus of several studies shown in Table 2. This interest stems from preclinical models indicating a synergistic mode of action of SN-38 and CPIs. Irinotecan plus an anti–PD-L1 antibody was shown to have a supra-additive antitumor effect in mouse models possibly due to irinotecan augmenting CPI-mediated T-cell activation (69). SG can also increase Forkhead box class 03a activity (Forkhead box transcription factors may be interconnected with Trop-2), which may suppress PD-L1 expression in breast tumors via activation of NK cells (70, 71). This indicates that SG may enhance CPI activity.

Positive results have already been shown with SG plus pembrolizumab in the phase II EVOKE-02 study in metastatic non–small cell lung cancer; the preliminary objective response rate (ORR) was 75% (95% confidence interval, 35–97) in eight patients with PD-L1 tumor proportion score ≥50% (72). Similar findings were observed with interim data from Morpheus-pan BC in which patients with mTNBC received atezolizumab with nab-paclitaxel (n = 9) or SG (n = 30); the ORR was 77% (atezolizumab plus SG) versus 67% (atezolizumab plus nab-paclitaxel), and the median (immature) progression-free survival (PFS) was 12.2 versus 5.9 months, respectively (73). Preliminary results from 104 patients with unresectable locally advanced or metastatic HR⁺/HER2⁻ breast cancer enrolled in the SACI-IO study are also promising (74). There was a trend toward improved median PFS with SG plus pembrolizumab versus SG alone (8.4 vs. 6.2 months, respectively), which was greater in patients with PD-L1–positive tumors (11.1 vs. 6.7 months).

SG has the potential to work synergistically with PARP inhibitors to prevent PARP-mediated single-strand DNA repair and improve antitumor effects (75, 76). SN-38 also mediates pro-apoptotic signals such as the upregulation of p21^WAF1/Cip1 and cleavage of procaspase-3 and PARP in TNBC cell lines (14). A phase II study evaluated sequential SG and talazoparib in 26 patients with mTNBC who received a median of two prior therapies for metastatic disease; the median PFS was 6.2 months, and the overall survival was 18 months (77). The most common grade ≥3 TRAEs were neutropenia (81%) and anemia (35%). Administration of the combination was feasible with prophylactic use of growth factor; the dosing schedule used was not associated with dose-limiting toxicities. In light of these findings, this approach warrants further investigation.

SG plus alpelisib in locally recurrent or metastatic HER2⁻ breast cancer is currently being evaluated in the ASSET study (NCT05143229). SG plus berzosertib (a potent, first-in-class inhibitor of ataxia telangiectasia–mutated–mediated DNA damage response and Rad3-related protein kinase (ATR; NCT04826341) is under investigation in small cell lung cancer resistant to PARP inhibitors.

Other interesting combinations include ADC–ADC. The double ADC (DAD) phase I study examined the effect of SG plus enfortumab vedotin (EV), an ADC that exerts its effects against nectin-4 with a microtubule inhibitor payload (monomethyl auristatin E); this approach highlights the potential to combine ADCs with different targets as well as payloads with different mode of actions. The DAD study enrolled 23 patients with metastatic urothelial carcinoma who had progressed on platinum and/or immunotherapy (78). The ORR was 70% (95% confidence interval, 47%–87%), and no new safety signals were identified. Multiple doses were studied and SG 8 mg/kg plus EV 1.25 mg/kg on days 1 and 8 of a 21-day cycle was selected as the recommend dose for further investigation in phase II studies in urothelial cancer. The authors are also investigating first-line SG and EV plus pembrolizumab in metastatic urothelial carcinoma as an additional cohort (DAD-IO). ADC–ADC sequencing is another key avenue for future work. One retrospective study evaluated SG and trastuzumab deruxtecan sequencing in 179 heavily pretreated patients with mBC; the findings from this paper highlight that a subset of patients benefit from ADC–ADC sequencing; a prospective randomized study would be needed to validate these findings (79). We also note that other Trop-2–directed ADCs are under development. These include sacituzumab tirumotecan (MK-2807/SKB264), datopotamab deruxtecan, and ESG401.

Finally, SN-38 may exert effects via other mechanisms currently under investigation. It inhibits far upstream element-binding protein activity and prevents it from binding to target DNA sequence FUSE. Far upstream element-binding protein 1 is a key oncoprotein involved in proliferation and antiapoptotic effects across a range of solid tumors and is overexpressed in more than 80% of hepatocellular carcinomas (80).

Conclusions

SG was designed to deliver a potent therapeutic payload to the tumor site via its ability to recognize and bind to Trop-2, which is highly expressed on a range of solid tumors. Its key properties include the following: (i) a unique construct with payload–linker dynamics that enable SN-38 to remain intact during circulation with maximal release in the acidic tumor lysosome, which also limits off-target toxicity; (ii) a linker that allows high DAR (∼8:1) to ensure internalization of sufficient SN-38 to kill the tumor cell; and (iii) the bystander effect – in which free SN-38 can subsequently enter neighboring tumor cells regardless of their Trop-2 expression. Additional studies exploring use in earlier lines of therapy and synergistic combinations may increase our understanding of the benefit of SG for patients with solid tumors.

Supplementary Material

Table S1

Supplementary Table S1: Summary of currently available antibody-drug conjugates

Table S2

Supplementary Table S2: Efficacy outcomes in sacituzumab govitecan studies

Author’s Disclosures

S.M. Tolaney reports nonfinancial support and other support from Parexel/Gilead Sciences, Inc., during the conduct of the study, as well as grants and personal fees from Novartis, Merck, AstraZeneca, Genentech/Roche, Eisai, Bristol Myers Squibb, Daiichi Sankyo, and Menarini/Stemline; grants, personal fees, and other support from Pfizer (SeaGen), Eli Lilly, and Gilead Sciences, Inc.; personal fees and other support from Sanofi, Jazz Pharmaceuticals, and Arvinas; personal fees from CytomX Therapeutics, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Aadi Bio, Bayer, Incyte Corp., Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, BioNTech, Johnson & Johnson/Ambrx, Launch Therapeutics, Zuellig Pharma, and Bicycle Therapeutics; and grants from Exelixis, NanoString Technologies, and OncoPep outside the submitted work. No disclosures were reported by the other authors.